Immunopathological reactions to drugs are important immunologic diseases and, at the same time, offer valuable opportunities to investigate human immune responses and immunopathologic reactions to biochemically defined antigens. Recent experiments in this laboratory have demonstrated that IgE, IgM, IgG, and IgA antibodies to the N4-sulfamethoxazoyl determinant are detectable in many individuals who have experienced adverse reactions during therapy with sulfamethoxazole (SMX). The objectives of the proposed experiments are to systematically characterize human immune responses to the N4-sulfamethoxazoyl hapten and to determine the role of these responses in the diverse clinical adverse reactions to SMX. Five groups of experiments will be performed. The first will explore the hypothesis that reactive metabolites or SMX, formed within a cell expressing appropriate oxidative enzymes, haptenate specific proteins in the same cell during protein synthesis or secretion. Analysis of cultured cells exposed to SMX and of circulating haptenated cells and proteins in treated humans will be performed. The second group of studies will extend these initial experiments and will test the hypothesis that haptenation and expression of immunopathologic reactions to SMX are related to an individual's ability to acetylate versus oxygenate the drug at the N4 site. The third group of studies will address the hypothesis that the immune responses detected are hapten specific and not influenced by specific macromolecular carriers. Cross reactions among N4-haptens formed from other sulfonamides will be studied and the potential for systemic hapten inhibition will be investigated. The fourth group of studies will assess specific antibody and lymphocyte responses following treatment with SMX to test the hypothesis that immune responses to SMX are the basis for many of the clinical adverse reactions. The relationship of specific immune responses to specific clinical phenomena will be explored. Finally, a skin model of sustained drug allergy will be developed, analyzed and used as a model of human mixed immunopathology. the data obtained from the described studies should provide valuable new insights into the mechanisms of haptenation, human immune responses, and immunopathology.